1. Field of the Invention
This invention is related to 2-substituted piperidine analogs. The analogs are selectively active as antagonists of N-methyl-D-aspartate (NMDA) receptor subtypes. The invention is also directed to the use of 2-substituted piperidine analogs as neuroprotective agents for treating conditions such as stroke, cerebral ischemia, central nervous system trauma, hypoglycemia, anxiety, convulsions, aminoglycoside antibiotics-induced hearing loss, migraine headaches, chronic pain, glaucoma, CMV retinitis, psychosis, urinary incontinence, opioid tolerance or withdrawal, or neuro-degenerative disorders such as lathyrism, Alzheimer's Disease, Parkinsonism and Huntington's Disease.
2. Related Background Art
Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acids (EAA) glutamate and aspartate at the N-methyl-D-Aspartate (NMDA) receptor. This excitotoxic action is considered responsible for the loss of neurons in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery and cerebral trauma, as well as lathyrism, Alzheimer's Disease, Parkinson's Disease and Huntington's Disease.
Various classes of substituted piperidine analogs are known. For example, U.S. Pat. No. 5,036,077 generically discloses piperidine derivatives described by the formula: ##STR1## wherein Ar represents a phenyl group substituted by R.sub.2, R.sub.3 and R.sub.4 or a naphth-1-yl or naphth-2-yl group, substituted or unsubstituted by 1 or 2 halogen atoms; X represents an oxygen atom or sulfur atom; R.sub.1 represents H or a halogen atom; R.sub.2 represents a halogen atom, a trifluoromethyl group, a phenyl group which is unsubstituted or substituted by 1 to 3 halogen atoms, a phenoxy group which is unsubstituted or substituted by 1 to 3 halogen atoms, or a C.sub.1 -C.sub.4 alkyl group and the benzyl group substitutes the piperidine radical in the 2, 3 or 4 position. This reference does not exemplify 2-substituted piperidines. The piperidines are said to be useful as antimicrobial agents, but there is no disclosure or suggestion of treating disorders responsive to selective NMDA receptor subtype antagonists.
Canadian Patent No. 696,999 is directed to N-(alkylene)aryl-2-substituted piperidines useful as vasodilators which are described by the formula: ##STR2## wherein A is an alkylene group having 2 to 3 carbon atoms. There is no mention of using the compounds of this reference as NMDA receptor antagonists or treating disorders responsive thereto.
PCT International Publication Number WO 93/15052 generically describes compounds that are said to be calcium channel antagonists represented by the formula: ##STR3## and the salts thereof, wherein R is C.sub.1-8 alkyl(phenyl)p, C.sub.2-8 alkenyl(phenyl)p, C.sub.2-8 alkynyl(phenyl)p, C.sub.3-8 cycloalkyl or C.sub.1-8 alkyl C.sub.3-8 cycloalkyl;
p is 0 to 2; PA1 n is 0 to 6; PA1 m is 0 to 6; PA1 A is a bond, --CH.dbd.CH--, --C.tbd.C--, oxygen, sulphur or NR.sup.1 ; PA1 R.sup.1 is hydrogen, C.sub.1-8 alkyl or phenyl C.sub.1-4 alkyl; and PA1 Ar is aryl or heteroaryl, each of which may be optionally substituted. 2-[2-(3,4-Dichlorophenoxy)ethyl]-1-cinnamylpiperidine oxalate hemihydrate and 4-[2-(2-Dibenzofuranyloxy)ethyl]-1-cinnamylpiperidine oxalate are exemplified. The compounds of this reference are said to be useful for treating anoxia, ischaemia, such as stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases and drug addiction withdrawal. This reference does not disclose or suggest NMDA receptor activity, let alone selective NMDA receptor subtype antagonism. PA1 Ar, D and R are selected from the group consisting of ##STR7## and in addition, R may have the values: ##STR8## cycloalkyl or loweralkyl, and D may have additionally the values: ##STR9## Ar (CH.sub.2).sub.1-4, X, Y and Z are selected from the group consisting of hydrogen, lower alkyl, halogen, ##STR10## z is one or zero with the proviso that z cannot be zero at the same time n is zero when one of the following occurs at the same time that D is phenyl or substituted phenyl: (A).sub.d is hydrogen, (A).sub.d is cyano, (A).sub.d is aminocarbonyl, or a double bond forms between the .alpha. carbon and a carbon of the central heterocyclic amine-ring; R.sup.1 is selected from hydrogen, loweralkyl, phenyl and phenylloweralkyl; R.sup.2 is selected from loweralkyl, phenyl and phenylloweralkyl; M is a pharmaceutically acceptable metal ion and the pharmaceutically acceptable salts thereof, including acid addition salts, quaternary salts, and hydrates and alcoholates thereof. This reference discloses that such compounds may be useful as coronary vasodilators, antihypertensives, antiarrhythmic, antiallergy, antihistamic and antisecretory agents. No compounds substituted at the 2 position of the piperidine ring are exemplified nor is there any disclosure or suggestions of NMDA antagonistic activity. PA1 Excitatory amino acid receptor antagonists that block NMDA receptors are recognized for usefulness in the treatment of disorders. NMDA receptors are intimately involved in the phenomenon of excitotoxicity, which may be a critical determinant of outcome of several neurological disorders. Disorders known to be responsive to blockade of the NMDA receptor include acute cerebral ischemia (stroke or cerebral trauma, for example), muscular spasm, convulsive disorders, neuropathic pain and anxiety, and may be a significant causal factor in chronic neurodegenerative disorders such as Parkinson's disease [T. Klockgether, L. Turski, Ann. Neurol. 34, 585-593 (1993)], human immunodeficiency virus (HIV) related neuronal injury, amyotrophic lateral sclerosis (ALS), Alzheimer's disease [P. T. Francis, N. R. Sims, A. W. Procter, D. M. Bowen, J. Neurochem. 60 (5), 1589-1604 (1993)] and Huntington's disease. [See S. Lipton, TINS 16 (12), 527-532 (1993); S. A. Lipton, P. A. Rosenberg, New Eng. J. Med. 330 (9), 613-622 (1994); and C. F. Bigge, Biochem. Pharmacol. 45, 1547-1561 (1993) and references cited therein.]. NMDA receptor antagonists may also be used to prevent tolerance to opiate analgesia or to help control withdrawal symptoms from addictive drugs (Eur. Pat. Appl. 488,959A). PA1 each R.sup.1 is independently hydrogen, alkyl or hydroxy; PA1 each R.sup.2 is independently hydrogen, alkyl or hydroxy; PA1 X is --CH.sub.2 --, O, S or NR.sup.3, wherein R.sup.3 is hydrogen or a lower alkyl group having 1 to 6 carbon atoms; PA1 Y is --CH.sub.2 --, --CH.dbd.CH--, --C.tbd.C--, O, S or NR.sup.3 ; PA1 m is 0, 1 or 2; and PA1 n is 0, 1, 2, 3, 4 or 5, PA1 provided that when m is 0 and X is --CH.sub.2 --, or m is 1, R.sup.1 is H and X is --CH.sub.2 -- that either Y is not --CH.sub.2 -- or at least one of R.sup.2 is not hydrogen and further provided that when Y is --C.dbd.C-- then X is not O. PA1 each R.sup.1 is independently hydrogen, alkyl or hydroxy; PA1 each R.sup.2 is independently hydrogen, alkyl or hydroxy; PA1 X is --CH.sub.2 --, O, S or NR.sup.3, wherein R.sup.3 is hydrogen or a lower alkyl group having 1 to 6 carbon atoms; PA1 Y is --CH.sub.2 --, --CH.dbd.CH--, --C.tbd.C--, O, S or NR.sup.3 ; PA1 m is 0, 1 or 2; and PA1 n is 0, 1, 2, 3, 4 or 5. PA1 each R.sup.1 is independently hydrogen, alkyl or hydroxy; PA1 each R.sup.2 is independently hydrogen, alkyl or hydroxy; PA1 Q is --C.dbd.C-- or --C.tbd.C--; PA1 Z is --CH.sub.2 --, O, S or NR.sup.3 ; PA1 m is 0, 1 or 2; and PA1 n is 0, 1, 2, 3, 4 or 5, provided that when Q is --C.dbd.C-- then Z is not O. PA1 *2-Benzyl-1-(2-phenoxy)ethylpiperidine; PA1 *2-Benzyl-1-(2-(4-trifluoromethyl)phenoxy)ethylpiperidine; PA1 **2-Benzyl-1-(2-(3-amino)phenoxy)ethylpiperidine PA1 **2-(4-chlorophenyl)methyl-1-(2-(3-amino)phenoxy)ethylpiperidine; PA1 **2-Benzyl-1-(3-phenoxy)propylpiperidine; PA1 *2-Benzyl-1-(3-(4-trifluoromethyl)phenoxy)propylpiperidine; PA1 *2-(4-chlorophenyl)methyl-1-(3-(3-amino)phenoxy)propylpiperidine; PA1 **2-Benzyl-1-(4-phenoxy)butylpiperidine; PA1 *2-Benzyl-1-(4-(3-trifluoromethyl)phenoxy)butylpiperidine; PA1 *2-Benzyl-1-(4-(3-amino)phenoxy)butylpiperidine; PA1 2-Benzyl-1-(4-(2-trifluoromethy)phenoxy)butylpiperidine; PA1 **2-Benzyl-1-(4-(4-trifluoromethyl)phenoxy)butylpiperidine; PA1 **2-Benzyl-1-(4-(3-fluoro)phenoxy)butylpiperidine; PA1 2-Benzyl-1-(3-(3-phenyl)propynyl)piperidine; PA1 *2-Benzyl-1-[3-(4-trifluoromethyl)phenyl)propynyl]piperidine; PA1 *2-(4-chlorophenyl)methyl-1-[4-(3-amino)phenyl)butynyl]piperidine; PA1 **2-Benzyl-1-[2-hydroxy-3-(2-methyl)phenoxy]propylpiperidine; PA1 **2-[(2-Ethoxy)phenoxy]methyl-1-(3-phenoxy)propylpiperidine; PA1 *2-[(2-Ethoxy)phenoxy]methyl-1-(3-(3-amino)phenoxy)propylpiperidine; PA1 *2-[(2-Ethoxy)phenoxy]methyl-1-(3-(4-trifluoromethyl)phenoxy)propylpiperidi ne; PA1 *2-[(2-Ethoxy)phenoxy]methyl-1-(3-(4-trifluoromethyl)phenyl)propylpiperidin e; PA1 **2-Benzyl-1-(5-phenoxypentyl)piperidine; PA1 **2-Benzyl-1-(2-(4-nitrophenoxy)ethyl)piperidine; PA1 **1-(2-(4-Aminophenoxy)ethyl)-2-benzylpiperidine; PA1 **2-Benzyl-1-(2-(4-amino-3-nitrophenoxy)ethyl)piperidine; PA1 **2-Benzyl-1-(2-(2-oxobenzimidazol-5-oxy)ethyl)piperidine; PA1 **2-(4-Chlorobenzyl)-1-(2-(4-fluorophenoxy)ethyl)piperidine; PA1 **2-(4-Chlorobenzyl)-1-(2-(4-hydroxyphenoxy)ethyl)piperidine; PA1 **2-Benzyl-1-(2-(4-hydroxyphenoxy)ethyl)piperidine; PA1 **2-Benzyl-1-(2-(4-hydroxyphenoxy)propyl)piperidine; PA1 **2-Benzyl-1-(2-(4-hydroxyphenoxy)butyl)piperidine; and PA1 2-[(4-chloro)phenoxy]methyl-1-(3-phenoxy)propylpiperidine. PA1 *1,2-Dibenzylpiperidine; PA1 2-Benzyl-1-(4-fluorophenyl)methylpiperidine; PA1 2-Benzyl-1-(4-trifluoromethylphenyl)methylpiperidine; PA1 *2-(4-chlorophenyl)methyl-1-(4-trifluoromethylphenyl)methylpiperidine; PA1 2-Benzyl-1-(2-phenyl)ethylpiperidine; PA1 2-Benzyl-1-(2-(3-fluoro)phenyl)ethylpiperidine; PA1 *2-Benzyl-1-(2-(4-trifluoromethyl)phenyl)ethylpiperidine; PA1 **2-(4-chlorophenyl)methyl-1-(2-(4-fluoro)phenyl)ethylpiperidine; PA1 **2-(4-chlorophenyl)methyl-1-(2-(3-amino)phenyl)ethylpiperidine; PA1 **2-Benzyl-1-(3-phenyl)propylpiperidine; PA1 *2-Benzyl-1-(3-(4-trifluoromethyl)phenyl)propylpiperidine; PA1 **2-(4-chlorophenyl)methyl-1-(3-(3-trifluoromethyl)phenyl)propylpiperidine; PA1 **2-Benzyl-1-(4-phenyl)butylpiperidine; PA1 *2-Benzyl-1-(4-(3-trifluoromethyl)phenyl)butylpiperidine; PA1 **2-(3,4-dichlorophenyl)methyl-1-(4-(4-trifluoromethyl)phenyl)butylpiperidi ne; PA1 *2-Benzyl-1-(2-phenoxy)ethylpiperidine; PA1 *2-Benzyl-1-(2-(4-trifluoromethyl)phenoxy)ethylpiperidine; PA1 **2-Benzyl-1-(2-(3-amino)phenoxy)ethylpiperidine PA1 **2-(4-chlorophenyl)methyl-1-(2-(3-amino)phenoxy)ethylpiperidine; PA1 **2-Benzyl-1-(3-phenoxy)propylpiperidine; PA1 *2-Benzyl-1-(3-(4-trifluoromethyl)phenoxy)propylpiperidine; PA1 *2-(4-chlorophenyl)methyl-1-(3-(3-amino)phenoxy)propylpiperidine; PA1 **2-Benzyl-1-(4-phenoxy)butylpiperidine; PA1 *2-Benzyl-1-(4-(3-trifluoromethyl)phenoxy)butylpiperidine; PA1 *2-Benzyl-1-(4-(3-amino)phenoxy)butylpiperidine; PA1 2-Benzyl-1-(4-(2-trifluoromethy)phenoxy)butylpiperidine; PA1 **2-Benzyl-1-(4-(4-trifluoromethyl)phenoxy)butylpiperidine; PA1 **2-Benzyl-1-(4-(3-fluoro)phenoxy)butylpiperidine; PA1 2-Benzyl-1-(3-phenyl)propynyl)piperidine; PA1 *2-Benzyl-1-[3-(4-trifluoromethyl)phenyl)propynyl]piperidine; PA1 *2-(4-chlorophenyl)methyl-1-[4-(4-(3-amino)phenyl)butynyl]piperidine; PA1 **2-Benzyl-1-[2-hydroxy-3-(2-methyl)phenoxy]propylpiperidine; PA1 **2-[(2-Ethoxy)phenoxy]methyl-1-(3-phenoxy)propylpiperidine; PA1 *2-[(2-Ethoxy)phenoxy]methyl-1-(3-(3-amino)phenoxy)propylpiperidine; PA1 *2-[(2-Ethoxy)phenoxy]methyl-1-(3-(4-trifluoromethyl)phenoxy)propylpiperidi ne; PA1 *2-[(2-Ethoxy)phenoxy]methyl-1-(3-(4-trifluoromethyl)phenyl)propylpiperidin e; PA1 **2-Benzyl-1-(5-phenoxypentyl)piperidine; PA1 **2-Benzyl-1-(2-(4-nitrophenoxy)ethyl)piperidine; PA1 **1-(2-(4-Aminophenoxy)ethyl)-2-benzylpiperidine; PA1 **2-Benzyl-1-(2-(4-amino-3-nitrophenoxy)ethyl)piperidine; PA1 **2-Benzyl-1-(2-(2-oxobenzimidazol-5-oxy)ethyl)piperidine; PA1 **2-(4-Chlorobenzyl)-1-(2-(4-fluorophenoxy)ethyl)piperidine; PA1 **2-(4-Chlorobenzyl)-1-(2-(4-hydroxyphenoxy)ethyl)piperidine; PA1 **2-Benzyl-1-(2-(4-hydroxyphenoxy)ethyl)piperidine; PA1 **2-Benzyl-1-(2-(4-hydroxyphenoxy)propyl)piperidine; PA1 **2-Benzyl-1-(2-(4-hydroxyphenoxy) butyl)piperidine; and PA1 2-[(4-chloro)phenoxy]methyl-1-(3-phenoxy)propylpiperidine.
European Patent Application No. 235,463 generically discloses calcium antagonists represented by the formula ##STR4## wherein; p is zero, one or two; ##STR5## m is zero to six inclusive; ##STR6## d and n are selected from zero or one and the dotted lines represent double bonds which may form consistent with the valence of carbon;
U.S. Pat. No. 5,192,799 generically disclosed amines described by the formula: ##STR11## wherein R.sub.3 -R.sub.4 can be taken together to form 4- to 8-membered ring and substituted by aryl, benzyl and heteroaryl. No 2-benzylpiperidine was exemplified in this reference. The compounds are said to be useful for the treatment and prevention of heart diseases. But there is no disclosure or suggestion of treating disorders responsive to selective NMDA receptor subtype antagonists.
European patent application No. 649838 generically disclosed cyclized amines described by the formula: ##STR12## wherein the nitrogen heterocycles can be 3-8 member rings and substituted in the 2-4 positions. Ar and Ar' are opt. mono or disubstituted phenyl. No. 2-benzylpiperidine was exemplified in this reference. The compounds are said to be useful to treat arrhythmia and tachycardia. But there is no disclosure or suggestion of treating disorders responsive to selective NMDA receptor subtype antagonists.
Japanese patent application No. 04217945 disclosed amines described by the formula: ##STR13## wherein R.sub.4 -R.sub.5 can be taken together to form 5- to 8-membered ring and substituted by benzyl and phenyl. The compounds are said to be useful as antiulcer agents. But there is no disclosure or suggestion of treating disorders responsive to selective NMDA receptor subtype antagonists.
U.S. Pat. No. 5,169,855 generically discloses disubstituted piperidine ether derivatives for use as antipsychotic agents selective for sigma receptors. Similarly, PCT International Publication No. WO 92/18127 and PCT International Publication No. WO 91/06297 generically disclose N-phthalimidoalkyl piperidines which are useful as antipsychotic agents and which are selective for sigma receptors. However, 2-substituted piperidines are not exemplified by any of these references and there is no mention of NMDA receptor activity.
Numerous references have disclosed piperidine derivatives substituted at the 4 and 3 position for use in a variety of treatments. Such references include, for example, U.S. Pat. No. 3,255,196 (3 and 4-substituted piperidines that are active antitussives and possess analgesic, antiemetic and local anaesthetic properties); U.S. Pat. No. 5,202,346 (4-substituted piperidines that are Class III antiarrhythmic agents); PCT International Publication No. WO 92/02502 (3 and 4-substituted piperidines which are calcium channel blockers expected to be useful in the treatment of anoxia, ischemia including stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases and drug addiction); PCT International Publication No. WO 88/02365 (3 and 4-substituted piperidines that may be useful for treatment of mental disorders accompanying cerebrovascular disease); BE 860701 (4-substituted piperidines for use as vasodilators and .beta.-adrenergic inhibitors); FR 2681319 (4-substituted piperidines for use as neuroprotectors and anticonvulsants); and DE 2939292 (4-substituted piperidines for use as antiallergenic and antiinflammatory agents). None of these references discloses or suggest 2-substituted piperidine analogs or their use as selective NMDA receptor subtype antagonists.
Expression cloning of the first NMDA receptor subunit, NMDAR1 (NR1) in Nakanishi's lab in 1991 provided an initial view of the molecular structure of the NMDA receptor [Nature 354, 31-37 (1991)]. There are several other structurally related subunits (NMDAR2A through NMDAR2D) that join NR1 in heteromeric assemblies to form the functional ion channel complex of the receptor [Annu. Rev. Neurosci. 17, 31-108 (1994)]. The molecular heterogeneity of NMDA receptors implies a future potential for agents with subtype selective pharmacology.
Many of the properties of native NMDA receptors are seen in recombinant homomeric NR1 receptors. These properties are altered by the NR2 subunits. Recombinant NMDA receptors expressed in Xenopus oocytes have been studied by voltage-clamp recording, as has developmental and regional expression of the mRNAs encoding NMDA receptor subunits. Electrophysiological assays were utilized to characterize the actions of compounds at NMDA receptors expressed in Xenopus oocytes. The compounds were assayed at four subunit combinations of cloned rat NMDA receptors, corresponding to four putative NMDA receptor subtypes [Moriyoshi, et al. Nature 1991, 354, 31-37; Monyer et al, Science 1992, 256, 1217-1221; Kutsuwada et al, Nature 1992, 358, 36-41; Sugihara et al, Biochem. Biophys Res. Commun. 1992, 185, 826-832].
An object of this invention is to provide novel 2-substituted piperidine analogs which function as subtype-selective NMDA receptor antagonists.
A further object of this invention is to provide a pharmaceutical composition containing an effective amount of the 2-substituted piperidine analogs to treat cerebrovascular disorders responsive to the selective blockade of NMDA receptor subtypes.
Another object of this invention is to provide a method of treating disorders responsive to the subtype-selective NMDA receptor antagonists in an animal by administering a pharmaceutically effective amount of 2-substituted piperidine analogs.